Common Gene Variant Linked to African American SIDS

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Note that this study implies that a gene-environment interaction may be responsible for some cases of sudden infant death syndrome among African American children.

Advise parents who ask that the study is preliminary, being based on a case-control analysis and in vitro tissue experiments.

CHICAGO, Feb. 2 - African Americans carrying a common genetic variation that predisposes them to cardiac arrhythmia are at an increased risk of bearing children with a vulnerability to sudden infant death syndrome, investigators here reported.

Carrying two copies of the variant is associated with a 24-fold increase in the risk of SIDS, according to Leigh Plant, Ph.D., of the department of pediatrics at the University of Chicago's Pritzker School of Medicine.

The discovery of the association - in a case-control study of SIDS - also led to a possible mechanism that may explain at least some of the roughly 2,500 SIDS deaths that occur yearly in the U.S., Dr. Plant and colleagues reported in the February issue of the Journal of Clinical Investigation.

SIDS is likely to have several causes, but at least some cases seem likely to be the result of abnormalities in ion channel genes linked to a range of heart irregularities, the researchers noted.

In particular, the sodium channel gene SCN5A is associated with an eightfold increase in cardiac arrhythmia risk for African Americans carrying a single copy of a mutation dubbed Y1103.

The researchers studied tissue collected from 133 African American infants who died with a diagnosis of SIDS. Tissue samples from 1,056 African American adults with no known health problems acted as controls.

Analysis of the tissue found:

5% of the SIDS deaths had changes - some common and some rare - in the SCN5A gene.

Three of the 133 African American SIDS babies (2.3%) had two copies of Y1103, compared with only one of the 1,056 controls (0.1%).

Comparing the two frequencies gives an odds ratio for SIDS of 24.4, with a 95% confidence interval from 1.9 to 1,279.

The variant "seemed like a good candidate for a genetic difference that could contribute to SIDS," said Steven Goldstein, M.D., Ph.D., chairman of pediatrics at the University of Chicago, aq co-author.

But under normal conditions, Dr. Goldstein said, the variant did not affect how sodium ion channels function.

However, SIDS is known to have an environmental component. The well-known "Back To Sleep" campaign, which urges parents not to let their children sleep on their stomachs, is based on the assumption that babies sleeping on their bellies have more interrupted breathing, or apnea.

A consequence of apnea is acute respiratory acidosis. When the researchers tested the Y1103 sodium channels in acidic conditions lowering cytosolic pH to 7.0 and 6.7, they re-opened after wild-type channels had closed, allowing an abnormal sodium flow. In heart muscle, such changes are known to increase the risk of arrhythmia and death.

The implication, the researchers said, is that the variant gene appears "to confer susceptibility to acidosis-induced arrhythmia, a gene-environment interaction."

"The common polymorphism alone does not cause SIDS," Dr. Goldstein said "Our findings suggest, however, that it renders infants vulnerable to environmental challenges -- such as a long pause in respiration -- that are tolerated by children without the mutation."

In an accompanying commentary, Jonathan Makielski, M.D., of the University of Wisconsin in Madison said the finding, while important, is likely "just the beginning of determining the complex genetic basis for SIDS."

Dr. Makielski added, "In the years ahead, other genetic abnormalities may also be linked to SIDS." Also, other environmental factors than acidosis may play a role, such as adrenergic stimulation or elevated potassium levels.

Although the effects of the Y1103 variant can be suppressed by the anti-arrhythmic drug Mexitil (mexiletine), the current study needs to be replicated, and perhaps complemented by a prospective study, before it has clinical implications, the researchers said.

They proposed consideration of genetic screening. "This study leads us to consider genetic screening in African Americans for SCN5A S1103Y in at least three situations: infants with acute life-threatening events, siblings of SIDS victims, and couples that experience infertility or fetal demise," they wrote.

"Given the apparent increased risk, a comprehensive study of postmortem molecular analysis of approximately 2,000 SIDS cases (the number reported each year in the U.S.) is recommended. If replicated, prospective screening in a large cohort of African American infants should be considered."

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine

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